The present invention relates to triazines, compositions and medicaments containing the same, as well as processes for the preparation and use of such compounds, compositions and medicaments. Such triazines exhibit pharmacological activity at estrogen receptors alpha (ERα) and beta (ERβ).
Estrogens are endocrine regulators in the cellular processes involved in the development and maintenance of the reproductive system. Estrogens have also been shown to have important effects in many non-reproductive tissues such as bone, liver, the cardiovascular system, and the central nervous system. Estrogens exert their effects by binding to an intracellular steroid hormone receptor. After the receptor and bound ligand are translocated to the nucleus of the cell, the complex binds to recognition sites in DNA, which allows for the modulation of certain genes. Certain estrogens have demonstrated the ability to exhibit their biological activity in a “tissue-selective” manner, functioning as estrogen agonists in certain tissues, while acting as estrogen antagonists in other tissues. The term “selective estrogen receptor modulators” (SERMs) has been given to these molecules, examples of which include tamoxifen, raloxifene, lasofoxifene, clomiphene, and nafoxidine. The molecular basis for this tissue selective activity is not completely understood. However, it is thought to involve the ability of the ligand to place the estrogen receptor into different conformational states that allow for differential capabilities in recruiting coactivator and corepressor proteins as well as other important proteins involved in transcriptional regulation (see McDonnell, D. P., “The hmolecular pharmacology of SERMs”, Trends Endocrinol. Metab. 1999, 301-311).
Historically, it was thought that estrogens manifested their biological activity through a single estrogen receptor, now termed estrogen receptor alpha (ERα). However, a second subtype of estrogen receptor, termed estrogen receptor beta (ERβ), has recently been discovered (Kuiper G. G. J. M. et. al., WO 9709348; Kuiper, G. G. J. M. et al., “Cloning of a novel estrogen receptor expressed in rat prostate and ovary”, Proc. Natl. Acad. Sci. U.S.A. 1996, 5925-5930). ERβ is known to be expressed in humans (Mosselman, S. et. al., “ERβ: identification and characterization of a novel human estrogen receptor”, FEBS Lett 1996, 49-53). The discovery of this second subtype of estrogen receptor significantly increased the biological complexity of estrogen signaling and may be responsible for some, but not all, of the tissue-selective actions of the currently available SERMs.
Osteoporosis is characterized by the net loss of bone mass per unit volume. The consequence of this bone loss is failure of the skeleton to provide adequate structural support for the body, resulting in increased incidence of fracture. One of the most common types of osteoporosis is postmenopausal osteoporosis, which is associated with accelerated bone loss subsequent to cessation of menses and declining levels of endogenous estrogen in women. The inverse relationship between densitometric measures of bone mass and fracture risk, for peri- and postmenopausal women in the process of rapid bone loss due to declining levels of estrogen, has been clearly established (Slemenda, C. W. et al., “Predictors of bone mass in perimenopausal women, a prospective study of clinical data using photon absorptiometry”, Ann. Intern. Med. 1990, 96-101; Marshall, D. et. al., “Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures”, Br. Med. J. 1996, 1254-1259). Elderly women currently have a lifetime risk of fractures of ca. 75%, with a 40% risk of hip fracture for white women over age 50 in the United States. The economic burden from osteoporotic fractures is considerable because of the necessity of hospitalization. In addition, although osteoporosis is generally not thought of as life-threatening, the mortality within 4 months of hip fracture is currently 20 to 30%. Current therapies for postmenopausal osteoporosis include estrogen replacement therapy or treatment with other antiresorptive agents such as bisphosphonates or calcitonin. However, patient compliance is low with all these therapies due to undesirable side effects or lack of efficacy.
Cardiovascular disease is the leading cause of death among postmenopausal women. The preponderance of data suggests that estrogen replacement therapy in postmenopausal women reduces the risk of cardiovascular disease, although some studies have reported no beneficial effect on overall mortality (Barrett-Connor, E. et. al., “The potential of SERMs for reducing the risk of coronary heart disease”, Trends Endocrinol. Metab. 1999, 320-325). The mechanism(s) by which estrogens exert their beneficial effects on the cardiovascular system are not entirely clear, but are potentially linked to their effects on serum cholesterol and lipoproteins, antioxidant properties, vascular smooth muscle proliferation, and inhibition of arterial cholesterol accumulation (Barrett-Connor, E. et. al., “The potential of SERMs for reducing the risk of coronary heart disease”, Trends Endocrinol. Metab. 1999, 320-325; Cosman, F; Lindsay, R. “Selective estrogen receptor modulators: clinical spectrum”, Endocrine Rev. 1999, 418-434).
The effects of estrogens on breast tissue, particularly breast cancer, have been well documented. The tissue selective estrogen tamoxifen has conclusively been shown to decrease the risk of recurrent breast cancer, contralateral breast cancer, and mortality as well as increase the disease-free survival in patients with breast cancer at multiple stages of the disease (Cosman, F; Lindsay, R. “Selective estrogen receptor modulators: clinical spectrum”. Endocrine Rev. 1999, 418-434). However, the mixed agonist-antagonist profile of tamoxifen is not ideal and may have stimulatory effects on uterine cell populations, leading to a potential increase in uterine cancer. An improved therapy for the treatment of these cancers would be an estrogen with no agonist properties on any reproductive tissues.
The present inventors have now discovered a novel group of triazine compounds, which bind to and modulate estrogen receptor alpha and estrogen receptor beta. These compounds also show good tissue-selective estrogenic activity and are therefore of use in the treatment and/or prophylaxis of postmenopausal osteoporosis, estrogen-dependent breast cancer, and cardiovascular disease. These compounds are also indicated to be of use for the treatment and/or prophylaxis of other diseases including dyslipidemia, relief of menopausal vasomotor symptoms, uterine cancer, prostate cancer, prostate hyperplasia, urinary incontinence, atherosclerosis, uterine fibroid disease, aortic smooth muscle cell proliferation and endometriosis.